I am not predicting total doom when I say that the current treatment of infectious diseases is under serious threat due to the increasing prevalence of multi-drug-resistant (MDR) pathogens. But germs that have developed ways to escape antibiotic treatment are unquestionably a growing threat. Both the Centers for Disease Control (CDC) and the World Health Organization (WHO) have declared those bugs to be major threats to health. The CDC estimates that in the US, antibiotic-resistant pathogens result in about two million illnesses and at least 23,000 deaths per year. In the US at present, methicillin-resistant Staphylococcus aureus (MRSA) infections kill more people than HIV/AIDS and tuberculosis combined. The UK’s 2016 Review on Antibiotic Resistance estimated that the global impact of these pathogens amounted to about 700,000 deaths and a financial impact in the trillions of dollars. And on September 21, 2016 the United Nations General Assembly convened to discuss the problem of antibiotic resistance and stated that antibiotic resistance was “the greatest and most urgent global risk.”
So, in that context, the possibility that bacteriophages can be used to treat infectious diseases has been attracting a good deal of attention lately.
I will admit that although I knew a tiny bit about bacteriophages – i.e., that they constitute an abundant class of viruses that essentially eat bacteria – it was a long and excellent piece in The New Yorker (“A Healing Virus,” Dec 21, 2020) that alerted me to the possibility that phages could be a highly important contribution to infectious disease treatment. And that I should do some digging around and devote a Doc Gumshoe installment to the subject.
The New Yorker piece about bacteriophages included several quite detailed case histories as well as background on the historical development of phage treatment and a simplified explanation of the mechanism through which phages destroy bacteria. By “simplified” I do not mean “dumbed down.” It was couched in terms that would be understood by the average New Yorker reader – i. e., intelligent but not proficient in medical lingo. I will assume that the average Doc Gumshoe reader is more intelligent and attempt to describe, in somewhat more detail, how bacteriophages invade germs, use them for nourishment and reproduction, and then kill the bacteria.
One of the case histories describes the case of Tom Patterson, who is married to Steffanie Strathdee, an infectious disease epidemiologist at the University of California San Diego School of Medicine. I will recapitulate Tom Patterson’s experience with phage therapy. However, a particularly interesting and currently relevant aspect of his experience is that it was, at least in part, what triggered the establishment of the first phage therapy center in North America, the Center for Innovative Phage Applications and Therapeutics (IPATH) at U. C. San Diego, about which more later.
Early history of bacteriophage therapy
Considering that phage therapy today is not widely used or even widely discussed, it is interesting that the possibility that there was a mysterious something that attacked germs was first investigated in the last years of the 19th century. A British bacteriologist, Ernest Hankin, reported in 1896 that there was an unidentified substance in the waters of the Ganges and Jumna rivers in India that was eliminating from their waters the bacterium Vibrio cholera that is responsible for cholera epidemics, thus limiting the spread of the epidemic. A couple of years later, the Russian bacteriologist Nikolay Gamaleya noticed much the same phenomenon with the non-pathogenic Bacillus subtilis. (Note: Nikolay Gamaleya founded the institute that this year discovered the Sputnik V vaccine.) These investigators reported their findings, but did not explore further. Then, more than twenty years later, the English bacteriologist Frederick Twort suggested that the phenomenon, which he had also observed, was likely due to a virus. Again, Twort went no further and did not publish his findings.
It was not until about 1915 that the French-Canadian microbiologist Felix d’Herelle conducted specific experiments to identify and attempt to characterize whatever it was that was invisibly reducing those bacterial populations. D’Herelle was studying an outbreak of severe hemorrhagic dysentery among French troops stationed at Maisons-Lafitte on the outskirts of Paris during World War I. He collected samples of the feces of the patients with dysentery and passed these through porcelain filters that were fine enough to filter out all bacteria, thereby collecting a bacteria-free liquid. He then used this liquid as a medium to culture the Shigella strains that had caused the hemorrhagic dysentery, and spread the culture on an agar medium to observe the growth of the bacteria.
The observation that led to the specific identification of the bacterial killer was the appearance of completely bacteria-free areas within the agar medium. Something in the filtered fecal matter was clearing out the Shigella. D’Herelle proposed that the bacterial-clearing agent was a virus, which he dubbed “bacteriophages,” the word “phage” coming from the Greek phagein, meaning “eat” or “devour,” effectively identifying the virus as an entity that feeds on bacteria.
A few years after that, d’Herelle made the first known attempt to use phages as therapy. At the Hôpital des Enfants-Malades, he obtained a bacteriophage by the same method of feces filtration. To test its safety, he ingested it himself, as did his superior, Professor Victor-Henri Hutinel, as well as several interns. The phage was then administered to a 12-year-old boy who was ill with severe dysentery. The boy’s symptoms completely stopped after a single dose of d’Herelle’s anti-dysentery phage, and the boy was completely recovered after a few days.
Following the successful treatment of that patient, three more patients with bacterial dysentery were treated with a single dose of the phage preparation and began to recover within 24 hours.
Other successful instances of bacteriophage treatment of bacterial infections came in 1921 when a number of patients with skin lesions due to a staph infection began to regress about 24 hours after a phage was injected into surgically-opened lesions.
Phage therapy was used to treat a number of infectious diseases in the following years, including thousands of people in India who were infected with cholera or bubonic plague. The encouraging results from those efforts induced several companies to start commercial production of phages against various bacterial pathogens.
One of those commercial ventures was started by d’Herelle himself. His company produced bacteriophage preparations against several classes of bacterial infections. These were called Bacté-coli-phage (targeting Escherichia coli), Bacté-rhino-phage (active against pathogens that cause colds), Bacté-intesti-phage, Bacté-pyo-phage, and Bacté-staphy-phage. These were marketed by a company which later became L’Oréal. And in the US in the 1940s, the Eli Lilly company produced seven bacteriophage products to treat infections in humans, targeting staph, strep, E. coli, and several others.
The sources of bacteriophages that are active against the pathogens that cause human infections are often the effluents from humans affected by those infections. Phages need to be very narrowly targeted to be effective. The phage preparations marketed by commercial phage producers are usually phage cocktails – mixtures of several phages that go after one class of bacteria such as E. coli or Streptococcus pneumoniae. However, it is by no means a sure thing that the E. coli phage cocktail that is given to a patient will target the specific variety of E. coli that affects that specific patient. And attempting to harvest phages from the individual patient’s feces as a means of targeting the particular pathogen that affects that patient is a vain endeavor, because if that patient had a sufficient quantity of phages in his/her system that targeted the specific pathogen, that patient’s symptoms would be under control. The simple fact that the patient is suffering from those symptoms likely points to a depletion in phages.
A look at the cases described in The New Yorker piece will shed some light on this.
What do those case studies tell us?
First, the case of Tom Patterson, which was referred to earlier. He and his wife, Steffanie Strathdee, were on vacation in Egypt when Patterson developed a case that was diagnosed as acute pancreatitis. He was flown to Frankfurt, Germany, where it was determined that he also had an abscess which was infected with a deadly, drug-resistant strain of Acinetobacter baumanni. Of fifteen powerful antibiotics, only three had any effect on his infection, and those only a slight effect. He was then taken home to San Diego, where fairly quickly the pathogen demonstrated resistance to those last antibiotics – the antibiotics of last resort, as they are known. Soon, Patterson’s organs – heart, lungs, and kidneys – began to fail and he went into a coma. It seemed as though they were out of options for his treatment.
Strathdee and Robert Schooley, the physician attending Patterson, came across references to phage therapy while searching the literature for alternative treatment options for Patterson. They contacted bacteriophage researchers in several parts of the world to see if any of them had a phage that might attack the pathogen that was attacking Patterson. They received phages that had been isolated from sewage plants, from dirt in Texas, and from lagoons of swine and cattle manure. These phages were then cultured and grown in bulk, and the resulting solution was purified of bacteria. Schooley received approval from the FDA to pump some of those phage solutions into Patterson’s abdominal cavity and some other phage solutions directly into a vein.
Three days later, Patterson came out of his coma, and within a few months his infection was completely eradicated.
It was this experience that led to the launching of IPATH at U. C. San Diego, and the collection there of a library of phages. His near-miraculous recovery received a great deal of publicity, and quite soon messages came flooding in from people who were hoping that phage therapy would prove a solution to the resistant infections that were affecting them or their loved ones.
The second case, which I will describe more briefly, was Joseph Bunevacz. He developed an E. coli infection in his bloodstream, which persistently recurred after every antibiotic that was attempted. His treatment involved surgical procedures to attempt to locate the tissues where the E. coli infection lurked, and monthly visits to the emergency department to receive huge doses of antibiotics, which would only briefly subdue the infection.
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It was Bunavacz’s daughter who suggested that they try phage therapy, and it was then that Stephanie Strathdee became involved. The author of the New Yorker piece, Nicola Twilley, met Strathdee and Patterson, and went along with them on a phage hunt to a brackish wetlands called Batiquitos Lagoon, just north of San Diego, to collect sewage outflow that would be a likely source of phages. This unappealing liquid was then purified, much as had been done by d’Herelle a century earlier, by passing it through filters fine enough to remove, not only any solid contaminants, but all bacteria, permitting only water and any viruses to pass through. Again, as d’Herelle had done, this phage-containing medium was tested against E. coli cultures to determine whether that particular phage might be effective in destroying the E. coli. In the case of that particular phage sample, the answer was apparently “no,” although Nicola Twilley doesn’t come out and say so.
Later in the piece, however, we hear the latest news about Bunavacz’s treatment: researchers at the Baylor College of Medicine have isolated phages that are active against the particular strain of E. coli that was causing those stubborn infections. The picture has morphed from seemingly hopeless to quite hopeful, although we do not yet know the outcome.
The third case history concerns Napoleon Del Fierro, who was infected with Pseudomonas aeruginosa, which is a bacterium known for its tendency to develop resistance to a number of antibiotics. P. aeruginosa in particular is the culprit in many of the respiratory infections that affect hospitalized patients, particularly those on respirators. Infections that arise in connection with hospital treatment, known as nosocomial infections, are more likely to be caused by pathogens that have developed resistance due to their exposure to antibiotics.
Del Fierro had been suffering from congestive heart failure for about ten years when he had a heart pump installed just under his sternum. Very quickly, the whole area became infected with P. aeruginosa. There was a brief and unsuccessful attempt to treat the infection with antibiotics, but when that therapy failed, phage therapy was initiated. The phages administered to him had been derived from the waste-water facility at Walter Reed National Military Center, which prepared the treatment. Initially, there were hopeful signs, but the phage therapy, which was applied directly to Del Fierro’s heart pump, eventually failed and Del Fierro did not survive.
What conclusions about phage treatment can we draw from these cases?
These three cases were well chosen to characterize the current state of bacteriophage treatment and how it fits into infectious disease treatment in general. We can draw several general conclusions:
- First, that phage therapy will by no means be the first treatment option to be attempted. The patients who receive phage therapy will almost certainly have failed antimicrobial therapy and are getting phage therapy as a last resort.
- Second, that because these patients have failed antimicrobial therapy, and most likely several courses of antimicrobial therapy, their infections are severe and probably life-threatening. The likelihood is that phage therapy will almost exclusively be used in patients with similarly severe and life-threatening infections.
- Third, that when it is decided that the last and best available option is bacteriophage therapy, there is no phage preparation at the ready that will attack the particular strain of pathogen that is causing their infection. The phage treatment that they eventually receive will have been carefully chosen to match the specific pathogen, and will have been harvested and incubated for the specific infection.
- Finally, before the patient receives the phage, special FDA authorization needs to be secured, citing the circumstances that created the need for phage therapy in the specific case, including the failure of antimicrobial treatment and the evidence that the phage preparation will probably target and eliminate the pathogen.
It’s evident that phages are not going to be used in what is known as “empiric therapy” for an infectious disease. That phrase describes antibiotic/antimicrobial treatment without first identifying the specific pathogen that is causing the infection. For example, a few years ago I developed a nasty upper respiratory infection and went to our local urgent care facility on a Sunday morning, where after a fairly brief examination I was given a diagnosis of pneumonia. The immediate treatment was a prescription for a broad-spectrum antibiotic, with a follow-up X-ray to make sure the infection was cleared. Which it was, after about two days.
That’s empiric treatment, and a huge number of infections are treated in exactly that way. Since many antibiotics are fairly broad in spectrum – that is, they target several classes of pathogens – it make sense to get the treatment started as early as possible in the course of the infection rather than wait until the specific genus, species, sub-species, and strain of the pathogen can be identified, which could take several days, during which the infection could thrive and the patient get sicker.
Phages do not work that way, and in all likelihood will not work that way. The phage recognizes and attacks the specific pathogen, down to the individual strain. In other words, not E. coli or P. aeruginosa in general, but the particular strain that is infecting the patient. Empiric phage treatment is unlikely.
Fortunately, identifying the phage that recognizes the specific pathogen is not an overwhelmingly complicated task. It is done much in the same way that d’Herelle found the phage that attacked the Shigella that were causing the dysentery that he was able to treat a hundred years ago: culture the pathogen in a medium that will permit the pathogen to spread over the bottom of several Petri dishes, dab those cultures with small quantities of the phages that might possibly work and observe which particular phages attack the pathogens in the culture.
The starting point in the selection of phages is a “phage library” – a collection of phages from a variety of sources, classified as to which types of bacteria they target. In the case of the phage that cured Tom Patterson’s Acinetobacter baumanni infection, it would have been possible to collect a number of phages that targeted any of several strains of A. baumanni, test these phages against the specific strain that was causing Patterson’s infection, and then treat Patterson with that particular phage.
Another approach would be the creation of phage cocktails, which would be mixtures of several phages that address a single bacterial genus. That would be like giving Tom Patterson a mixture of whatever phages targeted A. baumanni hoping that one of them would hit the one causing his infection. That was the premise behind d’Herelle’s creation of those phage preparations that he was marketing – Bacté-coli-phage, targeting Escherichia coli, and several others.
No such phage cocktails, or indeed any phage therapy products, are approved for human use in the US or in the EU, although some phage preparations are used in the food industry and labeled by the FDA under the classification of “generally considered safe.” These can be used against several bacterial classes including Salmonella, Listeria, methicillin-resistant S. aureus (MRSA), and others. And in former Soviet Union nations, phage preparations are sold over-the-counter as treatment for a range of common infections.
What exactly are phages, anyway?
Phages are viruses that feed on bacteria and use them for reproduction. As with all viruses, they are not able to reproduce on their own, but must depend on a host for survival. In the case of phages, the host is necessarily a bacterial host. They bind to specific receptors on the host cell, using claw-like extensions to explore the bacterial surface and locate the receptors. They attach and penetrate the bacterial host, disrupt the host cell’s DNA and employ sections of the DNA to synthesize the phage’s genome. Within the host cell, they create multiple copies of the original viral particle. Then they burst through the host cell, killing the bacterium and releasing these viral particles into the immediate environment, where they will search out and attach to other bacteria, repeating the process. The number of separate viral particles generated within a single bacterium can range from a few to as many as a thousand.
Phages are by far the most abundant biological entities on the planet. One estimate of the number of phages is 1032. That’s ten with thirty-two zeros. There’s no name for a number that large. They kill between 15% and 40% of all the bacteria in the world’s oceans every day. Scientists have identified 21,000 kinds of phages living in the human digestive system. As you can imagine, that presents a sort of challenge to scientists that are trying to find the phage that will attack a particular pathogen. However, as I said, checking whether a particular phage attacks a particular pathogen is not such a complicated process, so the quest is far from hopeless.
Here is a picture of a phage, copied from Wikipedia:
The appendages at the bottom of the picture are referred to as “tail fibers,” which the artist has depicted as somewhat spider-like. The phage uses those to seek out and connect to the receptors on the bacterial surface. The straight part above the tail is what injects the phage DNA into the bacterial host, where the replication occurs. The head does not enter the bacterial host – only the phage DNA.
When the phage matches the pathogen, the extermination of the pathogen takes place fairly quickly and efficiently, without any adverse effects on the patient. The difficult part of the process is making the match between the phage and the pathogen – not because there is anything particularly tricky in determining whether a particular phage will attack a particular pathogen, but because there are such a huge number of phages to be considered.
Considering the current state of phage therapy, what can we anticipate?
Will bacteriophage therapy become a mainstream infectious disease option?
I will take the liberty of venturing my own opinion about the future of antibiotic/antimicrobial treatment. As I see it, for the next twenty years or more, antibiotics will be the first option for the treatment of almost all infectious diseases.
The main reason is that most antibiotics/antimicrobials are broad in spectrum, meaning that they treat several pathogens, so in many cases they can be prescribed as soon as the patient demonstrates symptoms. Compared with the time-consuming (and thus expensive) process of isolating the correct phage to treat an infection, antibiotics are cheap. Physicians, pharmacists, and the general public are familiar and mostly comfortable with antibiotics. Whether the general public would ever feel comfortable with a substance derived from sewage is a major question. It comes down to substituting a new, expensive treatment that comes from a distasteful source (and which also requires the patient to go through a lot of tests) for a well-established, inexpensive, and familiar treatment that the patient can start right away. For the foreseeable future, antibiotics/antimicrobials will be the mainstay of treatment. Bacteriophage treatment will be used only in cases where all available antibiotics have failed.
Another obstacle facing phage treatment is the current regulatory status, which in the US would require special FDA approval each time a phage was used for treatment in a patient. That would persist unless an individual phage or a phage cocktail went through the FDA process to be approved for use. There are a number of obstacles that would have to be overcome for phage treatment to gain FDA approval.
Perhaps the most difficult of these would be conducting the necessary clinical trials. Phase 1 wouldn’t present much of a challenge, but by Phase 2 it would become necessary to test the phage in comparison with placebo in trial subjects that actually had an infectious disease. In the case of a phage, it would be absolutely necessary to precisely identify the pathogen that was causing the infectious disease of each subject in the clinical trial and narrow the enrollment criteria such that only subjects whose infections were caused by the specific pathogen that the phage being studied in the trial addressed were included in the study. Since these studies are blinded, such analysis would have to be carried out with regard to every subject in the trial, whether these subjects were to be treated with the active phage or with placebo. Giving a course of phage treatment without determining that the phage was active against the pathogen in vitro would be utterly useless.
Another major roadblock is that it would be extremely difficult to recruit clinical trial subjects with an infectious disease who would have to consent to an untried treatment derived from sewage, when there is a range of available antibiotics. The only individual patients likely to volunteer for such a trial would be patients who have already failed to respond to antibiotic treatment. And would such patients agree to a trial in which they might receive placebo?
My guess is that trials of that sort would not be sanctioned by the FDA. That means that the requirements for gaining FDA approval of phage therapy would need to be revised extensively. This will not happen quickly and may not happen at all.
In the meantime, the situation regarding antibiotics and resistant pathogens shows little signs of improvement. An obvious tactic to stay ahead of the pathogens would be to develop new drugs that, at least for a time, overcame the resistance of pathogens and successfully treated infectious diseases. But the development of new antibiotics has slowed to a crawl. For example, in the four years between 1983 and 1987, sixteen new antibiotics were approved by the FDA, but in a six-year time span between 2010 and 2016 only six new antibiotics crossed the finish line to FDA approval. And there is very little incentive for pharmaceutical companies to invest the huge sums – more than $2 billion – that getting FDA approval on a single drug ultimately costs, including developing the drug and conducting the necessary clinical trials. That is because new, effective antibiotics tend to be held back for use only in cases where other drugs have failed. They become drugs of last resort, and the drug developers have little chance of recovering their huge investment.
A way forward for phage therapy would be the creation of phage cocktails, as described above, that reliably attack a broader range of pathogens, such that it would not be necessary to identify the exact bacterium that was causing a patient’s infection. If a phage combination were to exist that effectively eliminated the most pathogenic species within the Streptococcus genus, it would be relatively simple to determine that a pathogen of that genus was the culprit, and treat